Proposed is a continuation of a cohort study on the natural history of HIV infection among injection drug users (IDUs) in Baltimore, MD known as the ALIVE study. Ongoing since 1988, this cohort of disadvantaged, primarily African American IDUs has provided critical epidemiological, clinical, pathogensis and behavioral data on the course of untreated and then treated HIV infection. Showing that highly active antiretroviral therapy (HAART) has reduced AIDS and related mortality; we note an increasing burden of non-AIDS outcomes. While this cohort has and continues1 to be a platform for an array of studies all critical to addressing questions about HIV infection in this population, this proposal emphasizes two major areas: 1) to determine the impact of HIV infection, HAART, and continuing drug abuse on non-AIDS age-associated outcomes. A primary hypothesis to be evaluated is that HIV infection accelerates progression of HCV-related liver disease; this is mediated by duration of HIV infection, degree of immunosuppression, duration and response to HAART, and illicit drug use. 2) to refine determinants of HAART effectiveness in this population, extending our earlier work on access and adherence to include patterns of HAART use (e.g., inconsistent access, switching, interruptions), all leading to suboptimal HIV care. Primary hypotheses here are that individual (e.g.illicit drug use,regimen complexity, comorbidities), provider, and neighborhood-level factors contribute to HAART effectiveness and ultimately, laboratory and clinical outcomes (e.g., diminished virologic and immunologic responses, development of viral resistance, and progression to AIDS and death). To achieve these aims, we will continue follow-up of our cohort which has demonstrated high rates of follow-up. Each semiannual visit includes detailed interviews, physical examinations and venipuncture for assays and repository, supplemented by medical record review and linkages with multiple registries. To enrich our analyses, we continue a parallel protocol of HIV uninfected IDUs (ALIVE-2) to facilitate distinction of effects due to HIV,HAART and drug use. Likewise, we continue but also have expanded collaborations to address in more detail the fundamental questions of pathogenesis and the impact of treatment. The ALIVE study can address this next generation of questions among African American IDUs with the intent to contribute to improved epidemiological, clinical and basic science and respond to the changing HIV epidemic.